Tài liệu BIOCHEMICAL TARGETS OF PLANT BIOACTIVE COMPOUNDS A pharmacological reference guide to sites

BIOCHEMICAL TARGETS OF

PLANT BIOACTIVE COMPOUNDS

A pharmacological reference guide to

sites of action and biological effects

GIDEON POLYA

CRC PRESS

Boca Raton London New York Washington, D.C.

Library of Congress Cataloging-in-Publication Data

Polya, Gideon Maxwell.

Biochemical targets of plant bioactive compounds : a pharmacological reference

guide to sites of action and biological effects 1 Gideon Polya.

p. cm.

Includes bibliographical references and index.

ISBN 0-41 5-30829-1

1. Materia medica, Vegetable-Handbooks, manuals, etc. 2. Botanical

chemistry-Handbooks, manuals, etc. 3. Plant products-Handbooks, manuals, etc.

4. Pharmacology-Handbooks, manuals, etc. 5. Plants-Metabolism-Handbooks,

manuals, etc. I. Title.

RS164 .P766 2003

61 5l.32-dc21 2002155281

This book contains information obtained from authentic and highly regarded sources. Reprinted material

is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable

efforts have been made to publish reliable data and information, but the authors and the publisher cannot

assume responsibility for the validity of all materials or for the consequences of their use.

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Visit the CRC Press Web site at www.crcpress.com

O 2003 by CRC Press

No claim to original U.S. Government works

International Standard Book Number 0-41 5-30829- 1

Library of Congress Card Number 2002 15528 1

Printed in the United States of America 2 3 4 5 6 7 8 9 0

Printed on acid-free paper

Contents

List of tables

Preface

1 Plant defensive compounds and their molecular targets

I. I Introduction I

1.2 Organization and scope ofthe book 2

1.3 Descr$tion of the tables 3

1.4 Using the tables 6

1.5 The structural diversiiy of plant defensive compounds 6

1.6 Plant alkaloids 8

1.7 Plantphenolics 21

1.8 Plant te9enes 33

1.9 Other plant compounds 44

2 Biochemistry - the chemistry of life

2.1 Introduction - water-based l$ 52

2.2 Protein structure 53

2.3 Engmes and ligand-binding proteins 58

2.4 Metabolic strategies 66

2.5 Inhibition of biochemical processes by plant defensiue compounds 85

3 Neurotransmitter- and hormone-gated ion channels

3.1 Introduction - electrical signalling in excitable cells 86

3.2 Ionotropic neurotransmitter receptors - neurotransmitter-gatedzon channels 88

3.3 Structure and function of ionotropic receptors 88

4 Ion pumps, ligand- and voltage-gated ion channels

4.1 Introduction 123

4.2 Ion pumps 123

4.3 Voltage-gated Nui channels 125

4.4 Ligand-regulated and voltage-gated K'+ channels 126

4.5 Voltage-gated Ca" channels 126

vi Contents

4.6 Ligand-gated Ca" channels 126

4.7 Chloride transport and voltage-regulated chloride channels 127

5 Plasma membrane G protein-coupled receptors

5.1 Introduction - signalling via heterotrimeric Gproteins 157

5.2 G protein-coupled hormone and neurotransnzitter receptors 158

5.3 Hormones and neurotransmitters acting via G protein-coupled receptors 159

5.4 Activation of spec$c G protein-coupled receptors 160

5.5 Leucocyte and inzamnzation-related G protein-linked receptors 162

5.6 Other G protein-coupled receptors 164

6 Neurotransmitter transporters and converters

6.1 Introduction 231

6.2 Synthesis of neurotransmitters 232

6.3 Release of neurotransmittersjonz synaptic vesicles 233

6.4 Re-uptake of neurotransnzitters into neurons and synaptic vesicles 233

6.5 Neurotransmitter degradation 233

7 Cyclic nucleotide-, ca2+ - and nitric oxide-based signalling

7.1 Introduction 253

7.2 ~a" and calmodulin-dependent engymes 254

7.3 Ad~yiyl cyclase 255

7.4 Manbrane-bound and soluble guanyiyl cyclases 255

7.5 Nitric oxide synthesis 256

7.6 Cyclic AMP- and cyclic GMP-dependentprotein kinases 257

7.7 Protein kinase honzologies and phosphoprotein phosphatases 257

7.8 Cyclic nucleotide phosphodiesterases 258

8 Signal-regulated protein kinases

Introduction 295

Cyclic AMP-dependent protein kinase 296

Cyclic GMP-dependent protein kinase 29 7

Protein kinase C 298

Ca2+ -calnzodulin-dependent protein kinases 298

AMP-dependent protein kinase 299

Receptor !yrosine kinases 300

Protein kinase B 301

Cytokine activation oftheJAK'/STATpathw(/~ 302

Cell cycle control 303

Receptor serine/threonine kinases 303

Other protein kinases 303

Phosphoprotein phosphatases 304

9 Gene expression, cell division and apoptosis

9.1 Introduction 339

9.2 Regulation of gene expression in prokaryotes 339

9.3 Regulation of transcr$tion in eukaryotes 340

9.4 MA processing and translation 342

9.5 Control of translation 342

9.6 Protein processing and post-translational mody5cation 343

9.7 Protein targeting 343

9.8 Cell division and apoptosis 344

9.9 HIVI infection and HIVI replication 345

9.10 Plant compounds intefering with gene expression 345

Contents vii

339

10 Taste and smell perception, pheromones and semiochemicals

10.1 Introduction 396

1 0.2 Sweet taste receptors 39 7

10.3 Bitter taste receptors 397

10.4 Saliy taste perception 398

10.5 Sour taste perception 398

10.6 Umami jplutamate taste perception) 398

10.7 Odorant perception 398

10.8 Animal pheronzones and other animal bioactives produced by plants 399

10.9 Other plant senziochemicals affecting aninzal behaviour 399

10.10 Odoriferous animal metabolites of ingestedplant compounds 399

11 Agonists and antagonists of cytosolic hormone receptors

11.1 Introduction 452

11.2 Steroid hormones 452

11.3 Non-steroid cytosolic hormone receptor ligands 453

11.4 Plant bioactives affecting cytosolic receptor-mediated signalling 454

12 Polynucleotides, polysaccharides, phospholipids and membranes 487

12.1 Introduction 487

12.2 Po~ynucleotides 488

12.3 Poiysaccharides and 01ip.osaccharides 489

12.4 Phosphol$ids and membranes 490

13 Inhibitors of digestion and metabolism

13.1 Introduction 51 7

13.2 Giycohydrolases 51 7

13.3 Proteases 518

13.4 Giyco&sis and tricarboxylic acid cycle 522

13.5 Mitochondria1 electron transport and oxidative phospho~ylation 522

13.6 Gluconeogenesis 523

13.7 Solute translocation 524

... viii Contents

14 Anti-inflammatory, antioxidant and antidiabetic plant compounds

14.1 Introduction 595

14.2 Adhesion and movement of inzammatocy leucocytes 596

14.3 Chemokines 596

14.4 Phagocytosis 597

14.5 Kinins, ~ytokines, platelet activating factor and eicosanoids 598

14.6 Plant-derived anti-inJamnzatory conqounds 599

14.7 Diabetes nzellitus and plant antidiabetic compounds 599

14.8 Summary 601

Appendix: structures of key parent and representative compounds

Bibliography

Compound index

Plant genus index

Plant common names index

Subject index

Abbreviations

Tables

Nicotinic acetylcholine receptor agorlists and antagonists

Iorlotropic y-aminobutyric acid and benzodiazepirle receptors

Iorlotropic glutamate, glycirle and serotonin receptors

Sigma and vanilloid receptors

Ca'+-A~Pase, Hf, K+-ATPase and Naf, Kf -ATPase

Voltage-gated Na+ channel

Ligand- and voltage-gated K+ channels

Voltage- and ligand-gated Ca2+ channels and ~a+ /Ca2+ antiporter

CFTR, voltage-gated C1 channels and Naf -K+-'LC1 co-transporter

Adenosine receptors

Muscarinic acetylcholirle receptor

Adrenergic receptors

Dopamine receptors

Metabotropic GABA(B)-, glutamate- and serotonin-receptors

Opiate receptors

Leucocyte- and inflammation-related G protein-coupled receptors

Other G protein-linked receptors

G protein-interacting plant compounds

Synthesis of rleurotransmitters

Release of neurotransmitters from syrlaptic vesicles

Re-uptake of neurotransmitters into neurons and synaptic vesicles

Acetylcholinesterase

Morloamirle oxidase

Degradation of other neurotransmitters

Calmodulirl

Adenylyl cyclase and guanylyl cyclase

Nitric oxide synthesis

Cyclic nucleotide phosphodiesterases

Eukaryote protein kirlases

Activation of protein kirlase C by ~lant-derived phorbol esters

Receptor tyrosine kinase-mediated signalling

Phosphatidylirlositol 3-kinase

Phosphoproteirl phosphatases

Ribosome-inactivating polynucleotide aminoglycosidases

Protein synthesis

x Tables

DNA-dependent RNA and DNA synthesis and topoisomerases

Dihydrofolate reductase and thymidylate synthetase

HIV- 1 integrase and HIV- 1 reverse transcriptase

Actin, histone acetylase, histone deacetylase, cell division and tubulin

Apoptosis-inducing plant compounds

Sweet plant compounds

Bitter plant compounds

Sour (acid) tasting plant compounds

Odorant plant compounds

Animal pheromones and defensive agents occurring in plants

Some further plant-derived semiochemicals

Odoriferous human products of ingested plant compounds

Agonists and antagonists of cytosolic steroid hormone receptors

Cytosolic non-steroid hormone receptor agonists and antagonists

Polynucleotide-binding compounds

Lectins and polysaccharide hydrolases

Non-protein plant compounds permeabilizing membranes

Plant proteins directly or indirectly perturbing membranes

Inhibition of glycosidases by plant non-protein compounds

Plant a-amylase inhibitor (aAI) proteins

Plant polygalacturonase-inhibiting proteins

Inhibition of proteases by plant non-protein compounds

Inhibition of proteases by plant proteins

Oxidative phosphorylation and photophosphorylation

Multidrug resistance, glucose and other transporters

Various enzymes

Plant lipoxygenase and cyclooxygenase inhibitors

Antioxidant free radical scavengers

Pro-oxidant compounds

Antioxidant enzyme induction and pro-inflammatory blockage

Aldose reductase and aldehyde reductase inhibitors

Plant compounds with hypoglycaemic, antidiabetic and/or insulinotropic

effects

Preface

Plants defend themselves from other organisms by elaborating bioactive chemical

defences. This is the essential basis of the use of herbal medicines that still represents a

major therapeutic resort for much of humanity However, at the outset, it must be stated that

any plant that is not part of our evolved dietary cultures is potentially dangerous.

Commercial herbal medicinal preparations approved by expert regulatory authorities have a

significant place in mainstream conventional medicine and in complementary medicine.

The first and last message of this book on the biochemical targets of bioactive plant con￾stituents is that use of herbal preparations for medicinal purposes should only occur subject

to expert medical advice. In the language of popular culture, DO NOT TRY THIS AT

HOME!

This book arose from 40 years as a student, researcher and academic teacher in biochem￾istry, a discipline fundamentally informed by both chemistry and physiology. This book

is aimed at a very wide readership from biomedical researchers and practitioners to a

wide range of scientifically literate lay persons. Lay readers (notably high school and

university students and graduates) would range from everyone following public media

reports and discussions on health, environmental and other scientific matters to potential

readers of popular generalist scientific journals such as Scientzjc American or New Scientkt.

The scientific readership would include researchers, professionals, practitioners, teachers

and industry specialists in a wide range of disciplines including the life sciences,

ecology, nursing, naturopathy, psychology, veterinary science, paramedical disciplines,

medicine, complementary medicine, chemistry, biochemistry, molecular biology, toxicology

and pharmacology

This book condenses a huge body of information in a succinct and user-friendly way

Ready access to a goldmine of key chemical structure/plant source/biochemical

target/physiological effect data from a huge scientific literature is via a Plant Common

names index, a Plant genus index and a Compound index. Such information is obviously

useful for biomedical and other science specialists. The introductory chemical and biochem￾ical summaries will be very useful to students in these and allied disciplines. However, at

a universal, everyday level, one can also use the book to readily find out about the nature and

targets of bioactive substances in what you are eating at a dinner party Further, plants and

their constituents play an important part in human culture and the bed-time or aeroplane

reader will find a wealth of interesting snippets on the historical, literary, artistic and general

cultural impact of plant bioactive substances.

Many people have variously helped and encouraged me in this project, most notably my

wife, Zareena, my children Daniel, Michael and Susannah, my mother and siblings, recent

xii Preface

research collaborators, colleagues who have given computing and scientific advice and

further colleagues and other professionals who have read specific chapters. I must gratefully

acknowledge the profound influence of my late father, Dr John Polya. Any deficiencies of

this book are simply due to me and have occurred despite such helpful interactions.

Dr Gideon Polya

Department of Biochemistry, La Trobe University

Bundoora, Melbourne, Australia

August 2002

1 Plant defensive compounds and

their molecular targets

1.1 Introduction

Higher plants are sessile and are consumed by motile organisms, namely other eukaryotes

and prokaryotes. Plants defend themselves by physical barriers including cell walls at the cel￾lular level, by the waxy cuticle of leaves and by bark and thorns at the macroscopic level.

Plants also defend themselves from fungal and bacterial pathogens and animal herbivores

by elaborating a variety of bioactive secondary metabolites and defensive proteins. There

may be as marly as 100,000 different kinds of plant defensive compounds of which about

30,000 have been isolated and structurally characterized. Biochemical targets have been

determined in vitro or in viuo for some thousands of the defensive compounds isolated to date.

The word "target" is being used rather broadly and loosely here to encompass the molec￾ular sites of interaction demonstrated for such compounds. However, the demonstrated

binding of a plant compound to a protein in vitro or in viuo does not necessarily mean that this

particular interaction is actually the critical site of action of the defensive compound.

Further, a particular defensive compound may have multiple molecular sites of action and

may well have synergistic effects with other such compounds. This book is concerned with

the biochemical targets of plant defensive compounds.

This treatise has been designed to address a very wide audience ranging from scientifically

literate lay people to researchers in many disciplines and health professionals. Plant products

have had a huge impact on the way in which different human societies have developed, espe￾cially over the last twelve thousand years since the advent of agriculture. Thus, the evolution

of specific day-length and temperature requirements for plant development meant adapta￾tion of specific plants to particular latitudes. Accordingly, exploitation of "useful" plants

(and of domesticatable animals feeding upon them) would have spread rapidly on an

East-West axis. This contributed to the technological and military dominance of cultures of

the Eurasian axis in the colonial era (as opposed to those of the North-South long axis con￾tinents of Africa and the Americas) (Diamond, 1997).

Particular plant products have had a massive impact on human populations and cultures

in recent centuries as evidenced by the slave trade to the Americas (for the purposes of coffee,

sugar and cotton production), colonial conquest in the East (opium, indigo, tea, cotton and

preservative spices), African subjugation (slavery, cocoa, rubber and timber) and temperate

colonization (grain, cotton, timber and herbivore production). Notwithstanding the

European "Enlightenment", these economic expansions and social reorganizations (both

domestic and colonial) were accompanied by horrendous abuses connected with war and

famine (problems that are continuing today in the "New World Order").

Plants provide a bulk supply of carbohydrate (typically as seed or tuber starch) to support

the global human population that now totals 6 billion as compared to an estimated 1 million

2 1. Plant defensive compounds and their molecular targets

hunter-gatherers before the advent of agriculture-based civilization twelve thousand years

ago. However, plants also provide humanity with a variety of bioactive constituents used for

their taste, preservative, psychotropic or medicinal properties. Notwithstanding synthetic

sweeteners, non-plant preservatives and an explosion of psychotropic drugs and other phar￾maceuticals, plants are still major sources of such ameliorative and protective agents. While

the "Western" pharmaceutical global market reached a value of US8354 billion in 2000,

the total global herbal medicine market is currently about US830 billion. Herbal medicine

remains a major core recourse for the impoverished majority of the world's population.

Herbal medicinal traditions can be traced back to our primate forebears. Thus, parasite￾infected chimpanzees make recourse to particular plants, which they evidently associate with

symptomatic relief. Human cultures in general have accumulated medicinal protocols based

on use of plants, major traditions including Chinese medicine and Indian Ayurvedic herbal

medicine. As detailed in this book, in some instances, specific bioactive substances from med￾icinal plants (or derivatives of such compounds) have found application in conventional

medicine. Thus, the cardiotonic cardiac glycoside sodium pump (Naf, K+-ATPase)

inhibitors derived from the initial use for cardiac insufficiency of digitalis (dried leaves of the

foxglove, DZpitalispurpureumn).

Determining the molecular sites of action of bioactive medicinal plant constituents is

clearly important for establishing the chemical and physiological basis for herbal medicinal

efficacy, for quality control of commercial herbal preparations and for the discovery of "lead

compounds" for synthetic (or semi-synthetic) pharmaceutical development. Of course, it

must be recognized that medicinal plant efficacy may derive from complex synergistic effects

or even from quasi-placebo effects connected with the taste, mild effects and appearance of

the preparation. While recognizing these possible "holistic" complications, in order to find

out how such preparations work, it is clearly important to initially isolate, structurally char￾acterize and define the biochemical targets of plant bioactive substances.

1.2 Organization and scope of the book

The book has been devised and organized so that it can be used by a wide range of people

as (a) a textbook, (b) a user-friendly reference and (c) as a comprehensive summary of the

biochemical pharmacology of plant compounds. This book focuses specifically on purified

plant compounds (secondary metabolites and proteins) and the molecular entities (princi￾pally proteins) with which they interact in the target microbial pathogens and animal herbi￾vores. In contrast, there are many essentially ethnobotanical books that variously deal with

medicinal and psychotropic plants, detailing the nature, distribution, physiological effects,

chemical components (where known) and cultural significance of such plants. In addition,

there are many books that deal with purified and characterized plant defensive components

from a chemical structure perspective. The Merck Index (Budavari, 2001) and the

Phytochemical Dictionary (Harborne and Baxter, 1993) are notable examples of such

chemical compendia that were particularly useful in the writing of this book and indeed are

very useful adjuncts to the present work (especially for the chemical structures of plant

compounds).

This first chapter deals with the structural diversity of plant defensive compounds. Chapter 2

provides a succinct but comprehensive summary of the essentials of biochemistry (the

chemistry of living things). This biochemical review provides a detailed background for

understanding the nature and function of the targets of plant defensive metabolites and pro￾teins. The remainder of the book summarizes (mainly in table form) a wealth of information

1. Plant defensive compounds and their molecular targets 3

about the molecular targets which are mainly proteins (such as receptors and enzymes) but also

include polynucleotides (RNA and DNA), phospholipids and reactive oxygen species (ROS).

It will be apparent from a preliminary scan of this book that most of the biochemical tar￾gets are directly or indirectly concerned with cellular signalling, that is, the machinery

enabling cells to perceive and respond to extracellular signals. Obvious major differences

aside (e.g. the occurrence of chloroplasts in plants), the fundamental biochemical processes

of metabolism and replication in plants and the organisms that consume plants are very

similar. Accordingly, plants must be protected from compounds they produce that poison

metabolism and replication. Such protection is achieved, for example, by defensive com￾pounds being deposited extracellularly, being temporarily inactivated by chemical modification

(e.g. glycosylation) and being highly specific for the non-plant targets. However, a major

"strategy" that has evidently evolved in the defence of sessile plants against their mobile

enemies has been to impair signalling processes, that is, it is energetically more efficient for

plants to discourage rather than kill plant-consuming organisms.

1.3 Description of the tables

Most of the book is comprised of tables dedicated to specific targets or groups of targets of

plant defensive compounds. Target-related tables are grouped into specific chapters that are

prefaced by succinct summaries of the biochemistry of the targets. The tables in general have

three columns that are dedicated respectively to (a) compound name, synonym and general

chemical class, (b) plant sources of the compound together with common plant names of

well-known plants, plant family and the plant part involved and (c) the biochemical target

being considered, a measure of the affinity of the compound for the target, other biochemi￾cal targets and in uiuo cellular and physiological effects of the compound. The information

provided for any compound entry has been pared to a minimum and extensive use is neces￾sarily made of abbreviations that are defined within the text and at the end of the book.

It should be noted that the literature covered for this book was enormous and varied.

Accordingly, plant parts, numerous plant sources and compound affinities are not given in all

entries. Measures of the affinity of a compound for its target are given in various ways. ICjo

value (concentration for 50% inhibition of an enzyme, 50% displacement of a known ligarld

from the target molecule or 50% inhibition of an in viuo process) is routinely presented in

round brackets in micromolar units (pM; micromoles per litre; 10~"rnoles per litre).

Compound-target dissociation constant (A;,) or inhibitor-target dissociation constant

(inhibitor constant, Ki) (another measure of tightness of association) is presented in square

brackets in micromolar units. For simplicity, the ICjO, or Ki values (when provided) are

given as a simple number with the unit (pM) being assumed because most of these values are

indeed in the range of 1-100 pM. However, in cases when these values are much less than

1 pM, the value is given with the appropriate unit explicitly specified, for example, nM

(nanomolar; nanomoles per litre; 10~~'rnoles per litre) and pM (picomolar; picomoles

per litre; 10~"rnoles per litre). Of course, the quarltitation of such affinities depends upon

the conditions of measurement and the source of the biochemical target entity. However, it

was felt that provision of such values in many cases would give a useful "ball park" figure for

comparative purposes and for indicating concentrations required for in uitro or in uivo effects.

Thus (1 pM) would indicate that the compound binds very tightly to the target or causes

in uitro or in viuo effects at extremely low concentrations. Conversely, (100) (i.e. 100 pM) would

indicate a low affinity of the compound for the target and a relatively high concentration

being required for in vitro or in uivo effects.